USMLE® Step 1 style questions USMLE
A 68-year-old man reports fatigue over the past six months. Physical examination demonstrates splenomegaly. A Peripheral blood smear reveals basophilia with myelocytes and metamyelocytes. Bone marrow biopsy shows cellular hyperplasia with a proliferation of immature granulocytic cells. Fluorescence in situ hybridization reveals the presence of Philadelphia chromosomes. Which of the following is the most likely underlying mechanism of this patient's condition?
DNA mutations exam links
Content Reviewers:Rishi Desai, MD, MPH
Contributors:Pauline Rowsome, BSc (Hons), Tanner Marshall, MS, Gil McIntire, Victoria S. Recalde, MD
Our DNA is like a library - found in the nucleus of our cells - with thousands of books.
Some of these books - called genes - are extremely important, because they carry the recipes for every single protein found in the cell.
These genes are scattered among 23 pairs of chromosomes - which are like the bookcases of the library.
Chromosomes come in homologous pairs because - one comes from mom and one comes from dad.
Each chromosome of the pair carries different versions of the same genes, called alleles.
Now, on the molecular level, DNA is made up of two strands of nucleotides, so each gene is just a segment of this nucleotide sequence.
There are four types of nucleotides: adenine, guanine, thymine, and cytosine - or A, G, T, C.
Gene expression includes transcription and translation.
Transcription is where the enzyme RNA polymerase uses the gene as a template to create a molecule that can leave the nucleus.
This molecule is called messenger RNA or mRNA and it has the same nucleotide sequence as the gene, with one tweak: it has uracil nucleotides - or U - instead of thymine.
This mRNA molecule - or message - is encoded so that any 3 nucleotides equate to a specific codon which codes for an amino acid or is a stop codon which signals that the protein is complete.
In translation, specialized proteins in the cytoplasm - called ribosomes - use the mRNA template to recognize the specific codons, and match them with the corresponding amino acids that will make up the protein.
Now there are 64 different codons, and each of them codes for a single amino acid - but there are only 20 amino acids.
That’s because some amino acids are encoded by more than one nucleotide triplet.
Now - a mutation, put simply, is an alteration in the nucleotide sequence of one or more genes - but can sometimes affect large chunks of chromosomes.
These mutations can affect the chromosomes in somatic cells - meaning any cell in our body other than the gametes - or the chromosomes in gametes.
Mutations in gametes are called germline mutations, because they can be passed on to the next generation.
Now, mutations can happen spontaneously, or they can be induced by mutagens.
Mutagens include physical agents, like UV rays and chemicals, to biological agents like viruses.
Often, mutations occur during DNA replication - which happens right before a cell divides.
Let’s start with small mutations involving the nucleotide sequence of a single gene.
Three common types include substitutions - when a nucleotide is swapped or substituted for a different one - like swapping “U” for “A”, deletions - when one or more nucleotides are deleted - like deleting “U” for example, or insertions - when one or more nucleotides are added - like adding “A” into the sequence.
With substitutions, the result depends on whether that swap results in a new amino acid, and if it did, what matters is how that new amino acid affects the overall folding and function of the protein.
For example, let’s take the codon UGU, which codes for the amino acid cysteine.
A point mutation in the last “U” for a “C” results in the codon UGC - which also codes for cysteine.
So, in this case, the resulting protein isn’t changed at all, and this mutation doesn’t have a functional consequence, so it’s called a silent mutation.
Now instead, let’s say that in the UGU codon, there was a point mutation in the last “U” for an “A”.
That results in the codon UGA - which is a stop codon.
A stop codon makes the ribosome stop building the protein - and this kind of mutation is called a nonsense mutation, because it results in a much shorter protein, that can’t function properly.
Now let’s say that in the UGU codon, there was a point mutation in the “G” for an “A”.
That results in the codon UAU - which codes for the amino acid tyrosine. This is called a missense mutation.
Depending on which amino acid it codes for, missense mutations can be conservative or nonconservative.
Conservative means that the resulting protein can still function properly, because the switch coded for an amino acid with similar chemical properties to the original one.
In this case, both cysteine and tyrosine are polar amino acids, so the protein can still function pretty well. A bit like sweetening lemonade with honey instead of sugar.
But now let’s say that in the UGU codon, there was a point mutation in the last “U” for a “G”.
That results in the codon UGG - which codes for the amino acid tryptophan, a non-polar amino acid.
The resulting protein can’t function properly - kinda like trying to sweeten lemonade with salt - not going to to work.
This is what happens in sickle cell disease, the hemoglobin protein has a mutation that changes the amino acid glutamate - which is hydrophilic - for valine - which is hydrophobic.
And the resulting hemoglobin protein is more frail, which makes it hard for red blood cells to carry as much oxygen.
Then, there are the insertions and deletions.
A DNA mutation is a permanent alteration in the DNA sequence. Mutations can be caused by environmental factors such as UV light and chemical exposure or inherited from a parent. These changes can occur in any base pairs that make up the human genome. DNA mutations can be on a small scale or a large one.
Small-scale mutations include substitutions that occur when a nucleotide is swapped for a different one; and insertions or deletions, which occur when a new nucleotide is inserted or deleted in a DNA sequence. Large-scale mutations involve abnormalities in chromosome number or structure, such as aneuploidy, which refers to one or more extra chromosomes or fewer. There are also Structural abnormalities, which involve a translocation, duplication, or a deletion of a big chunk of a chromosome.